CC BY
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ОГЛЯДОВ1СТАТТ1
UDC УДК 618.19-006:591.134.5:613.25]-08-036.8:547.466.1(01) https://doi.Org/10.26641/2307-0404.2018.1.124953
M.I.M. Hojouj, BREAST CANCER AND BODY WEIGHT INDEX:
LN. Bondarenko, THE ROLE OF L-CARNITINE IN PREDICTION
MMFvA?1™']; OF ANSWER TO TREATMENT AND OUTCOME
T'.V.Ho02j OF TUMOR IN PATIENTS WITH OBESITY
Yu.N. Bondarenko, (review of literature)
N.E. Soloviova, Y.A. Shevchenko
SE «Dnipropetrovsk medical academy of Health Ministry of Ukraine»
Department of oncology and medical radiology
V. Vernadskii str., 9, Dnipro, 49044, Ukraine
ГУ «Днепропетровская медицинская академия МЗ Украины»
кафедра онкологии и медрадиологии
(зав. - д. мед. н., проф. И.Н. Бондаренко)
ул. В. Вернадского, 9, Днепр, 49044, Украина
e-mail: [email protected]
Key words: body mass index (BMI), breast cancer (BC), obesity, overall survival, L-carnitine
Ключевые слова: индекс массы тела (ИМТ), рак молочной железы (РМЖ), ожирение, общая выживаемость, L-карнитин
Abstract. Breast cancer and body weight index: the role of L-carnitine in prediction of answer to treatment and outcome of tumor in patients with obesity (review of literature). Hojouj M.I.M., Bondarenko I.N., Zavizion V.F., Artemenko M.V., Hojouj T.V., Bondarenko Yu.N., Soloviova N.E., Shevchenko Y.A. Increasing the effectiveness of antitumor therapy in breast cancer patients who take L-carnitine during preoperative systemic antitumor therapy compared with patients receiving standard neoadjuvant systemic antitumor therapy served as a prerequisite for studying possible antitumor mechanisms of L-carnitine. The positive effect of L-carnitine is due to the transfer ofpalm-n-fatty acid through the inner membrane into the mitochondrial matrix, which contributes to the formation of a significant number of ATP molecules. It has also been shown that L-carnitine can have a double protective effect, enhancing the energy dynamics of the cell and inhibiting the hyperexcitability of the cell membrane, making it an ideal tool for the prevention and treatment of complications of antitumor therapy and concomitant metabolic disorders. This work summarizes the results of epidemiological and clinical studies on the use of L-carnitine in the treatment of breast cancer.
Реферат. Рак молочной железы и индекс массы тела: роль L-карнитина в прогнозе ответа на лечение и исходе опухоли у больных с ожирением (обзор литературы). Ходжуж М.1.М., Бондаренко И.Н., Зави-зион В.Ф., Артеменко М.В., Ходжуж Т.В., Бондаренко Ю.Н., Соловьева Н.Е., Шевченко Ю.А. Повышение эффективности противоопухолевой терапии у больных РМЖ, которые принимают Ь-карнитин во время проведения предоперационной системной противоопухолевой терапии, по сравнению с пациентами, получающими стандартную неоадъювантную системную противоопухолевую терапию, послужило предпосылкой для изучения возможных противоопухолевых механизмов действия Ь-карнитина. Положительный эффект Ь-карнитина обусловлен переносом пальм-н-жирной кислоты через внутреннюю мембрану в матрикс митохондрий, что способствует образованию значительного количества молекул АТФ. Также доказано, что Ь-карнитин может иметь двойной защитный эффект, усиливая энергетическую динамику клетки и ингибируя гипервозбудимость клеточной мембраны, что делает ее идеальным средством для профилактики и лечения осложнений противоопухолевой терапии и сопутствующих метаболических нарушений. В данной работе приведены обобщенные результаты эпидемиологических и клинических исследований по изучению применения Ь-карнитина в лечении рака молочной железы.
The incidence of breast cancer in the world in general and in Ukraine in particular is growing. In 2017, in Ukraine the incidence reached 16 percent of female population, for which, the breast cancer ranked first in structure of oncological incidence among women.
In analysing the data of the National Cancer Registry of Ukraine, it should be noted, that in comparison with 2014 year, the prevalence rate of breast cancer in 2016 has increased by 5,1%, that indicates importance of improvement diagnostic procedures and methods of treatment it [1].
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Studying the scientific literature on this subject, we noticed that there is a strong biological relationship between obesity and a poor outcome of breast cancer. And having analysed the date of Ministry of Health in Ukraine it can be concluded, that about 26% of women in 2017 year had overweight or obesity [2]. More depressing results show WHO -in 2016 39% of adults over 18 years (39% of men and 40% of women) were overweight, while 13% of the adult population of the planet (11% of men and 15% of women) were obese [14].
Obesity has a chronic metabolic character, which is the result of the interaction of the endogenous factors, environmental conditions and lifestyle. Endogenous factors could be considered a violation of the genetic and hormonal balance. The external conditions and type of lifestyle include irregular rhythm nutrition, use of substandard products and sedentary lifestyle. Obesity is the first risk factor for metabolic syndrome, diabetes type II, cardiovascular disease and some forms of cancer, including breast cancer.
Since overweight is a risk factor for breast cancer, there is reason to believe that among patients with breast cancer the percentage of obese women is higher than in the population. The risk of breast cancer in postmenopausal women by 30%, it is more than in premenopausal, women with obesity - 50%. Furthermore it was proven that obesity is associated with poor prognosis in patients with breast cancer, regardless of menopausal status, and effectiveness of systemic medication breast cancer in patients that have overweight is lower than in patients with normal BMI [17].
Analyzing the statistics, it was noted that patients with breast cancer and normal BMI have a longer overall and disease-free survival, compared with patients with breast cancer and obesity. There is also a strong correlation between obesity and the involvement of lymph nodes in the cancer process. These observations show that obesity can enhance the metastatic spread of breast tumors [6, 7].
Although obesity is associated with a poor outcome in women with breast cancer, it is unclear how weight loss after diagnosis will change its course and results.
Recently, complementary and alternative medicine (CAM) is widely accepted among patients with breast cancer, which may provide several beneficial effects including reduction of therapy-associated toxicity, improvement of cancer-related symptoms, fostering of the immune system, and even direct anticancer effects [3].
L-carnitine is a metabolite of C4 oil LC, which is involved in the transfer of palm-n-LC through the inner membrane into the mitochondrial matrix and is
a substrate for the formation of ATP molecules. Carnitine is a trimethylated amino acid naturally synthesized in the liver, brain and kidneys from protein lysine and methionine. Several factors, such as sex hormones and glucagon, can influence the distribution and level of carnitine in tissues [2, 18].
In the absence of L-carnitine, the inner membrane of the mitochondria becomes impermeable to fatty acids, which entails a chain of various metabolic disorders in the human body. Carnitine has a modulating effect on the function of acetylcholine excitatory neurotransmitter, glutamate excitatory amino acid, insulin growth factor-1 (IGF-1) and nitric oxide (NO) [2].
Also proved, that L-carnitine may have a dual protective effect by enhancing the energy dynamics of the cell and inhibiting cell membrane hype-rexcitability, which make it an ideal nutrient for cancer prevention and treatment [18].
Based on the data that are already studied, it can be concluded that L-carnitine is the ideal medicine for treating the metabolic syndrome in obese people. There is a direct relationship between obesity and the risk of developing breast cancer. Based on the data of literature, it can be argued that this risk directly correlates with the severity of the metabolic syndrome and with BMI, which causes the urgency and need for more in-depth study of this problem.
This article presents the information of epide-miological and clinical studies of the influence of the body mass index on the effectiveness of breast cancer treatment by individualizing therapeutic measures taking into account the characteristics of patient's metabolism.
The effectiveness of the prescribing of L-car-nitine for breast cancers' treatment, as well as the effect of BMI on the outcome of the disease is proven in epidemiological and clinical studies.
DSM Chan and co-authors (2014) reported that women who have BMI>30 course and outcomes of breast cancer are significantly worse than women with BMI <30. They proved, that women with BMI> 30 have the overall relative risk of total mortality 1.41, women with BMI of 25>30 - 1.07. At the same time, for every 5 kg/m2 of the increase BMI, the risk of both total mortality and mortality from breast cancer increased, namely by 18% and 14%, respectively [5].
M. Protani and co-authors (2010) have shown that women with breast cancer, who are suffering in obesity, have lower survival rate than women with breast cancer without obesity [24].
Recently published data of randomized clinical reseaches by ML Neuhouser and co-authors (2015) demonstrated, that for women>50 years old, with 2
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and 3 stages of obesity (BMI>35) is typically the development of GR+ breast cancer [23].
Similarly, B. Pajares et al., who found significantly worse results for patients with BMI>35 compared with patients with BMI<25, stated that the magnitude of the effect depended on the cancer subtype (estrogen receptor (ER)/progesterone (PR) positive and HER2 negative, HER2 positive, triple negative) [21].
An analysis of the pooled data of the three adjuvant studies of the Eastern Cooperative Cancer Group showed significantly worse results for patients with obesity (BMI>30) than for patients with normal BMI with a hormonal receptor-positive disease. And it was noted absence of negative effect of obesity on survival in patients with other breast cancer subtypes [22].
C. Fontanella et al. (2015) studied the effect of BMI on different molecular subtypes of breast cancer and concluded that in women with ER / PR-positive and HER2-negative breast cancer, as well as with TNBC, the risk of death is significantly higher than in other subtypes of cancer. This is because the fatty tissue produces an excessive amount of estrogen, a high level of which is associated with an increased risk of developing breast, endometrial, ovarian and some other cancers. It has also been proven that the level of adipokine, that promotes cell proliferation, increases in the blood with increasing of level of fat in organism. And adiponectin, which people with obesity have less than people with normal BMI, can have antiproliferative effects. Such data can serve as evidence of the effect of BMI on the course and outcome of breast cancer [16].
Yet another proof of influence developing metabolic syndrome on the course and outcome of breast cancer was proposed by R. Bhandari et al. (2014). They proved, that that the presence of metabolic disorders (that is, the metabolic syndrome) is associated with an increased risk of breast cancer in adult women [4].
The above data led to the need to investigate medicines that contribute to fat burning, such as L-carnitine. Based on the data provided by Rania M. Khalil and co-authors (2013), we can prove the positive effect of this medicine on the course and outcome of breast cancer. The study showed that patients who received Tamoxifen with L-carnitine had significant decrease of Her-2 / neu and IGF-1 level (P<0.05) in the serum compared with patients who received only Tamoxifen. Using of L-carnitine led to significant decrease Her-2 / neu level in the serum (P<0.05) compared to each of the control patients, namely, 59.5%. The effect of tamoxifen on IGF-1 (P<0.05) -decrease its level by 5.4% [9].
However, it has been proved that using of L-carnitine in the treatment of ER+ breast cancer does not significantly reduce the level of estradiol, but leads to decrease both tumor markers CEA and CA15.3 (P <0.05,% decrease by 80.9% and 67,8%, respectively) [9].
Using of L-carnitine in patients with breast cancer and obesity improves the metabolism of fatty acids in mitochondria, restores normal mitochondrial function and, thus, improves the general condition and quality of patients' life [19].
Carnitine may also mimic some of the biological activities of glucocorticoids, particularily immunomodulation, via suppressing TNF-a and IL-12 release from monocytes (5). L-carnitine as adjuvant therapy in cisplatin-treated cancer patients proved a beneficial effect in reducing the cisplatin-induced organ toxicity [25].
It is possible that, the extremely lipophilic nature of carnitine may be responsible for the decrease in EGF binding [10]. Carnitine may insert in the cell membrane and/or interact with one of the many cellular enzymes having lipid substrates or cofactors. In addition, carnitine may interact directly with the EGFR [15].
Experimental evidence is available showing that active forms of oxygen may induce the ligand-independent phosphorylation of the EGFR activating Her-2/neu. Moreover, the expression of the receptor is induced in conditions of oxidative stress [20].
L-carnitine, via its free radical scavenging and antioxidant properties, may inhibit ROS-mediated EGFR phosphorylation. It has been found that palmitoyl-carnitine can inhibit the activity of heart and brain protein kinase C in a competitive manner and subsequent phosphorylation of the EGFR [8].
Although the tumor markers and IGF-1 showed no significant difference in TAM-treated patients before and after administration of L-CAR, there was a tendency to decline it after L-CAR supplementation [9].
The results of the above studies became a prerequisite for conducting clinical studies aimed at establishing the role of L-carnitine in the treatment of breast cancer. To date, the search in the online clinical research registration system Clini-calTrials.gov using key words L-carnitine + breast cancer has revealed several studies evaluating the efficacy and safety of L-carnitine in the treatment of breast cancer patients [9]. Analyzing the obtained results, we can conclude that L-carnitine was the medicine of choice for neuropathies, as a consequence of chemotherapy, in patients with breast cancer [13].
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CONCLUSIONS
L-carnitine is widely used in clinical practice. However, recently this medicine causes growing interest among oncologists. In a number of studies, L-carnitine has proven itself as a medicine that capable, during the preoperative systemic antitumor therapy, to increase its effectiveness compared with
standard neoadjuvant systemic antitumor therapy. To date, there are several clinical studies that are reseaching using L-carnitine in various malignant tumors, the results of which are the basis for further in-depth study of the effect of the medicine in the treatment of malignant neoplasms.
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